Division of Cancer and Developmental Biology, Institute of Molecular and Cell Biology, Singapore.
EMBO J. 2010 Sep 1;29(17):2994-3006. doi: 10.1038/emboj.2010.166. Epub 2010 Jul 23.
p53 mediates DNA damage-induced cell-cycle arrest, apoptosis, or senescence, and it is controlled by Mdm2, which mainly ubiquitinates p53 in the nucleus and promotes p53 nuclear export and degradation. By searching for the kinases responsible for Mdm2 S163 phosphorylation under genotoxic stress, we identified S6K1 as a multifaceted regulator of Mdm2. DNA damage activates mTOR-S6K1 through p38alpha MAPK. The activated S6K1 forms a tighter complex with Mdm2, inhibits Mdm2-mediated p53 ubiquitination, and promotes p53 induction, in addition to phosphorylating Mdm2 on S163. Deactivation of mTOR-S6K1 signalling leads to Mdm2 nuclear translocation, which is facilitated by S163 phosphorylation, a reduction in p53 induction, and an alteration in p53-dependent cell death. These findings thus establish mTOR-S6K1 as a novel regulator of p53 in DNA damage response and likely in tumorigenesis. S6K1-Mdm2 interaction presents a route for cells to incorporate the metabolic/energy cues into DNA damage response and links the aging-controlling Mdm2-p53 and mTOR-S6K pathways.
p53 介导 DNA 损伤诱导的细胞周期停滞、细胞凋亡或衰老，它受 Mdm2 调控，Mdm2 主要在核内泛素化 p53，促进 p53 核输出和降解。通过寻找在遗传毒性应激下负责 Mdm2 S163 磷酸化的激酶，我们鉴定出 S6K1 是 Mdm2 的多效调节剂。DNA 损伤通过 p38α MAPK 激活 mTOR-S6K1。激活的 S6K1 与 Mdm2 形成更紧密的复合物，抑制 Mdm2 介导的 p53 泛素化，并促进 p53 的诱导，此外还在 S163 上磷酸化 Mdm2。mTOR-S6K1 信号的失活导致 Mdm2 核易位，这得益于 S163 磷酸化、p53 诱导减少以及 p53 依赖性细胞死亡的改变。这些发现确立了 mTOR-S6K1 作为 DNA 损伤反应中 p53 的新型调节剂，可能在肿瘤发生中也是如此。S6K1-Mdm2 相互作用为细胞将代谢/能量信号纳入 DNA 损伤反应提供了一种途径，并将控制衰老的 Mdm2-p53 和 mTOR-S6K 途径联系起来。
